The illicit abuse of prescription opioid analgesics has been on the rise in recent years. This illicit use has been associated to the rewarding/reinforcing properties of opioid agonists. However, many prescription opioid analgesics contain a combination of two compounds: an opioid agonist, such as hydrocodone, plus a non-narcotic analgesic, such as acetaminophen. Although the combination analgesic formulations have been effective in treating pain, it is yet unknown whether the combined formulations possess greater rewarding properties, as compared to the opioid agonist alone, which may lead to greater use and abuse. Acetaminophen is not known to contain rewarding effects;however, it could possibly potentiate the rewarding properties of opioid agonists, such as hydrocodone, when combined. Interestingly, recent findings suggest that the analgesic actions of acetaminophen occur through its active metabolites. In particular, acetaminophen is metabolized into AM404, known to be a transporter blocker of the endocannabinoid anandamide, as well as an agonist for transient receptor potential vanilloid type 1 (TRPV1) receptors. We, therefore, hypothesize that acetaminophen will enhance/potentiate the rewarding properties of hydrocodone in rats through this novel mechanism. Therefore, in a series of experiments, we propose to address whether acetaminophen is able to enhance the rewarding properties of hydrocodone using the conditioned place preference paradigm. We will also address whether the enhancing effects of acetaminophen on hydrocodone reward can be blocked by prevention of AM404 formation. Lastly, we will address if the actions of acetaminophen on hydrocodone reward can be blocked by antagonism of CB1 or TRPV1 receptors. Funds provided by this funding opportunity can facilitate and supplement our current start-up research funds that have been provided by the College of Pharmacy at Western University of Health Sciences. PUBLIC HEALTH RELEVANCE: There has been a significant increase in the non-medical (illicit) use of prescription opioid analgesics in the United State over the past decade. Our project is set to determine whether prescription opioid analgesics that contain a combination of the two compounds, hydrocodone and acetaminophen (commercially known as Vicodin(R)), possess a greater rewarding effect than the individual drugs. The findings from this project will shed light on the abuse liability of drugs, such as Vicodin, and will advance our understanding as to why there has been an increase in the illicit use and abuse of prescription opioid analgesic drugs.